Cannabis use during adolescence leads to cognitive abnormalities. However, only some cannabis users display cognitive impairment, suggesting a genetic predisposition to the detrimental cognitive effects of cannabis. The mechanisms whereby genetic susceptibility interacts with cannabis exposure to produce cognitive dysfunction remain unknown. Cannabinoid receptor type 1 (CB1R) expressed in astrocytes mediates the adverse cognitive effects of delta-9-tetrahydrocannabinol (?9-THC), a major psychoactive ingredient of cannabis. In order to explore the molecular mechanisms of predisposition to cannabis effects, we will utilize our mouse model of astrocyte-specific inducible expression of dominant-negative Disrupted in Schizophrenia 1 (DN-DISC1). Our overarching hypothesis is that astrocytic DN- DISC1 and adolescent ?9-THC treatment synergistically up-regulates CB1R-mediated COX-2 signaling, leading to an increase in glutamate release and deficits in adolescent neuronal maturation and cognitive function. Specific Aim 1 will identify the critical period required for the synergistic cognitive effects of astrocyte-specific DN-DISC1 expression and chronic ?9-THC exposure. Specific Aim 2 will examine the synergistic effects of DN-DISC1 and ?9-THC on extracellular and tissue content of glutamate, GABA, and endocannabinoids. Specific Aim 3 will examine the synergistic effects of DN-DISC1 and ?9-THC on adolescent maturation of pyramidal neurons and GABAergic interneurons. Specific Aim 4 will identify the mechanisms by which up-regulation of COX-2 signaling synergistically induced by DN-DISC1 and ?9-THC exposure leads to increased glutamate release and cognitive dysfunction. Our proposed research will identify the molecular mechanisms of how adolescent cannabis use leads to cognitive impairment in susceptible individuals to facilitate an informed search for preventive treatments of long-term adverse effects of marihuana use.